Oral-facial clefts, particularly cleft lip with or without cleft palate (CL/P) are a major public health problem, affecting one in every 500-1000 births worldwide. Therefore, many research groups have attempted to identify genetic loci contributing to the etiology of CL/P, with limited success to date. There have been several allelic associations identified, and a few potentially linked markers; however, these results have not been consistent across study population. It appears that the genetic contribution to the etiology of oralfacial clefting is complex, possibly heterogeneous, or possibly due to interacting effects of multiple loci. Therefore, it is important to exploit the power of diverse study designs in an overall strategy aimed at identifying genetic loci involved in clefting. One very powerful study design for identifying linked genetic loci is homozygosity mapping within inbred affected individuals. This approach is particularly applicable to detecting recessive loci. Given a dense map of known genetic markers (approximately 10cM apart), only 3-10 inbred affected individuals are necessary to achieve a LOD score greater than 3, depending on the degree of consanguinity and the informativeness of the markers. Dense genome screening maps are now readily available, as are computer algorithms capable of rapid multipoint calculations in inbred families. Through collaboration with the Cleft Palate Clinic of Hacettepe University, Ankara, Turkey (which has a high proportion of consanguineous matings), we will ascertain a sample of inbred affected individuals. The overall goal of the study is to apply homozygosity mapping and simultaneous search techniques to identify recessive loci involved in CL/P. The specific aims of the study are therefore to: (1) Ascertain the study sample, a total of 325 individuals, comprising: 75 affected inbred individuals (CL/P); 150 parents of the affected individuals; 100 population-based, unaffected, unrelated controls. (2) Obtain blood samples and extract DNA from each of the study subjects. (3) Genotype each study subject for a dense genome-wide panel of known markers (10 cM spacing)--approximately 400 markers. (4) Apply multipoint, homozygosity mapping procedures, in a simultaneous search framework, to identify regions linked to clefting. (5) Use association analyses to identify any allelic associations. (6) Genotype additional markers in regions of possible linkage or association to confirm and to refine any positive results.